Transdermal and topical administration of local anesthetic agents using basic enhancers

ABSTRACT

Compositions and transdermal systems are provided for enhancing the permeability of skin or mucosal tissue to topical or transdermal application of local anesthetic agents. The compositions and systems include a base in order to increase the flux of the agent through a body surface while minimizing the likelihood of skin damage, irritation or sensitization. The permeation enhancer can be an inorganic or organic base. Methods of use are also described.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application is a divisional of U.S. Ser. No. 10/176,265filed on Jun. 19, 2002, which is a continuation in part of U.S. Ser. No.09/972,008 filed on Oct. 4, 2001, which is a continuation in part ofU.S. Ser. No. 09/738,410 filed on Dec. 14, 2000, which is a continuationin part of U.S. Ser. No. 09/569,889 filed on May 11, 2000, which is acontinuation in part of U.S. Ser. No. 09/465,098 filed on Dec. 16, 1999;and is a continuation in part of U.S. Ser. No. 09/738,395 filed on Dec.14, 2000, which is a continuation in part of U.S. Ser. No. 09/607,892filed on Jun. 30, 2000, now abandoned.

FIELD OF THE INVENTION

[0002] This invention relates generally to the topical and transdermaladministration of local anesthetic agents, and more particularly relatesto methods and compositions for enhancing the flux of local anestheticagents through a body surface utilizing a basic permeation enhancer.

BACKGROUND OF THE INVENTION

[0003] The delivery of drugs through the skin provides many advantages;primarily, such a means of delivery is a comfortable, convenient andnoninvasive way of administering drugs. The variable rates of absorptionand metabolism encountered in oral treatment are avoided, and otherinherent inconveniences, e.g., gastrointestinal irritation and the like,are eliminated as well. Transdermal drug delivery also makes possible ahigh degree of control over blood concentrations of any particular drug.

[0004] Skin is a structurally complex, relatively thick membrane.Molecules moving from the environment into and through intact skin mustfirst penetrate the stratum corneum and any material on its surface.They must then penetrate the viable epidermis, the papillary dermis, andthe capillary walls into the blood stream or lymph channels. To be soabsorbed, molecules must overcome a different resistance to penetrationin each type of tissue. Transport across the skin membrane is thus acomplex phenomenon. However, it is the cells of the stratum corneum,which present the primary barrier to absorption of topical compositionsor transdermally administered drugs. The stratum corneum is a thin layerof dense, highly keratinized cells approximately 10-15 microns thickover most of the body. It is believed to be the high degree ofkeratinization within these cells as well as their dense packing whichcreates in most cases a substantially impermeable barrier to drugpenetration. With many drugs, the rate of permeation through the skin isextremely low without the use of some means to enhance the permeabilityof the skin.

[0005] Numerous chemical agents have been studied as a means ofincreasing the rate at which a drug penetrates through the skin. As willbe appreciated by those in the field, chemical enhancers are compoundsthat are administered along with the drug (or in some cases the skin maybe pretreated with a chemical enhancer) in order to increase thepermeability of the stratum corneum, and thereby provide for enhancedpenetration of the drug through the skin. Ideally, such chemicalpenetration enhancers or “permeation enhancers,” as the compounds arereferred to herein, are compounds that are innocuous and serve merely tofacilitate diffusion of the drug through the stratum corneum. Thepermeability of many therapeutic agents with diverse physicochemicalcharacteristics may be enhanced using these chemical enhancement means.However, there are skin irritation and sensitization problems associatedwith high levels of certain enhancers.

[0006] There are many potential uses for topical and transdermaldelivery of local anesthetic agents. Such uses include the treatment ofbums, contact dermatitis, insect bites, pain, pruritus, skin rash,wounds and other dermal injuries; use as part of or in preparation for asurgical procedure; use as a pretreatment prior to needle injection,such as for subcutaneous injections, venipucture, and in particular forintramuscular or intrajoint injections such as for the administration ofcorticosteroids and other steroids, and so forth.

[0007] Accordingly, there is a need for a method that is highlyeffective in increasing the rate at which local anesthetic agentspermeate the skin, does not result in skin damage, irritation,sensitization, or the like, and can be used to effect transdermaldelivery of a wide range of compounds within the class of localanesthetic agents. It has now been discovered that basic permeationenhancers as described herein are highly effective permeation enhancers,and provide all of the aforementioned advantages relative to knownpermeation enhancers. Furthermore, in contrast to many conventionalenhancers, transdermal administration of local anesthetic agents withbasic permeation enhancers, employed at the appropriate levels, does notresult in systemic toxicity.

SUMMARY OF THE INVENTION

[0008] One aspect of the invention pertains to a method for enhancingthe flux of a local anesthetic agent through a body surface, comprising:(a) administering the local anesthetic agent to a localized region of ahuman patient's body surface; and (b) administering a basic permeationenhancer to the localized region, the enhancer comprising apharmaceutically acceptable base and being present in an amounteffective to provide a pH within the range of about 8.0-13.0 at thelocalized region of the body surface during administration of the agentand to enhance the flux of the agent through the body surface withoutcausing damage thereto. The pharmaceutically acceptable base can be aninorganic or an organic base.

[0009] Another aspect of the invention relates to a composition for theenhanced delivery of a local anesthetic agent through a body surface,comprising a formulation of: (a) a therapeutically effective amount ofthe local anesthetic agent; (b) a pharmaceutically acceptable base in anamount effective to provide a pH within the range of about 8.0-13.0 atthe body surface during administration of the agent and to enhance theflux of the agent through the body surface without causing damagethereto; and (c) a pharmaceutically acceptable carrier suitable fortopical or transdermal drug administration. In one aspect of theinvention the pH is about 8.0-11.5 and in another aspect, the pH isabout 8.5-10.5. The formulation is typically aqueous. Thepharmaceutically acceptable base can be an inorganic or an organic base.

[0010] Yet another aspect of the invention pertains to a system for theenhanced topical or transdermal administration of a local anestheticagent, comprising: (a) at least one drug reservoir containing the localanesthetic agent and a pharmaceutically acceptable base, in an amounteffective to enhance the flux of the local anesthetic agent through thebody surface without causing damage thereto; (b) a means for maintainingthe system in agent and base transmitting relationship to the bodysurface and forming a body surface-system interface; and (c) a backinglayer that serves as the outer surface of the device during use, whereinthe base is effective to provide a pH within the range of about 8.0-13.0at the body surface-system interface during administration of the localanesthetic agent. In one aspect of the invention the pH is about8.0-11.5 and in another aspect, the pH is about 8.5-10.5. Thepharmaceutically acceptable base can be an inorganic or an organic base.

DETAILED DESCRIPTION OF THE INVENTION

[0011] The present invention provides a method for enhancing the flux oflocal anesthetic agents through a body surface. A local anesthetic agentand a basic permeation enhancer are administered to a localized regionof a human patient's body surface. The permeation enhancer is apharmaceutically acceptable base and is present in an amount effectiveto: a) provide a pH within the range of about 8.0-13.0 at the localizedregion of the body surface during administration of the drug and b)enhance the flux of the local anesthetic agent through the body surfacewithout causing damage thereto. Examples of suitable permeationenhancers are described below. The local anesthetic agent and thepermeation enhancer may be present in a single pharmaceuticalformulation, or they may be in separate pharmaceutical formulations.

[0012] The steps of (a) administering the local anesthetic agent and (b)administering the basic permeation enhancer can be done in any order.For example, step (a) can be done prior to step (b); step (b) can bedone prior to step (a); and steps (a) and (b) can be donesimultaneously. Certain methods may be preferred depending upon theselection of the local anesthetic agent and basic permeation enhancer,as well as taking into consideration ease of patient compliance and soforth. For example, performing steps (a) and (b) simultaneously, is onepreferred method of the invention.

I. Definitions and Nomenclature

[0013] Before describing the present invention in detail, it is to beunderstood that this invention is not limited to particular drugs ordrug delivery systems, as such may vary. It is also to be understoodthat the terminology used herein is for the purpose of describingparticular embodiments only, and is not intended to be limiting. Inaddition, before describing detailed embodiments of the invention, itwill be useful to set forth definitions that are used in describing theinvention. The definitions set forth apply only to the terms as they areused in this patent and may not be applicable to the same terms as usedelsewhere, for example in scientific literature or other patents orapplications including other applications by these inventors or assignedto common owners. Additionally, when examples are given, they areintended to be exemplary only and not to be restrictive.

[0014] It must be noted that, as used in this specification and theappended claims, the singular forms “a,” “an” and “the” include pluralreferents unless the context clearly dictates otherwise. Thus, forexample, reference to “a pharmacologically active agent” includes amixture of two or more such compounds, reference to “a base” includesmixtures of two or more bases, and the like.

[0015] In describing and claiming the present invention, the followingterminology will be used in accordance with the definitions set outbelow.

[0016] “Active agent,” “pharmacologically active agent” and “drug” areused interchangeably herein to refer to local anesthetic agents. Theterms also encompass pharmaceutically acceptable, pharmacologicallyactive derivatives and analogs of local anesthetic agents, including,but not limited to, salts, esters, amides, prodrugs, active metabolites,inclusion complexes, analogs, and the like. Therefore, when the terms“active agent,” “pharmacologically active agent”, “drug” or “localanesthetic agent” are used, it is to be understood that applicantsintend to include the active local anesthetic agent per se as well aspharmaceutically acceptable, pharmacologically active salts, esters,amides, prodrugs, active metabolites, inclusion complexes, analogs,etc., which are collectively referred to herein as “pharmaceuticallyacceptable derivatives”.

[0017] The term “aqueous” refers to a composition, formulation or drugdelivery system that contains water or that becomes water-containingfollowing application to the skin or mucosal tissue.

[0018] The term “base” is used in its traditional sense, i.e., asubstance that dissolves in water to produce hydroxide ions. The wateris typically an aqueous fluid, and may be natural moisture at the skinsurface, or the patch or composition that is used may contain addedwater, and/or be used in connection with an occlusive backing.Similarly, any liquid or semisolid formulation that is used ispreferably aqueous or used in conjunction with an overlayer of anocclusive material. Any base may be used provided that the compoundprovides free hydroxide ions in the presence of an aqueous fluid. Basescan provide free hydroxide ions either directly or indirectly and thuscan also be referred to as “hydroxide-releasing agents”.Hydroxide-releasing agents that provide free hydroxide ions directly,typically contain hydroxide groups and release the hydroxide ionsdirectly into solution, for example, alkali metal hydroxides.Hydroxide-releasing agents that provide free hydroxide ions indirectly,are typically those compounds that are acted upon chemically in anaqueous environment and the reaction produces hydroxide ions, forexample metal carbonates or amines.

[0019] “Body surface” is used to refer to skin or mucosal tissue.

[0020] “Carriers” or “vehicles” as used herein refer to carriermaterials suitable for transdermal or topical drug administration.Carriers and vehicles useful herein include any such materials known inthe art, which are nontoxic and do not interact with other components ofthe composition in a deleterious manner.

[0021] “Effective amount” or “a therapeutically effective amount” of alocal anesthetic agent is intended to mean a nontoxic but sufficientamount of the local anesthetic agent to provide the desired therapeuticeffect. The amount that is effective will vary from subject to subject,depending on the age and general condition of the individual, theparticular local anesthetic agent being administered, and the like.Thus, it is not always possible to specify an exact effective amount.However, an appropriate effective amount in any individual case may bedetermined by one of ordinary skill in the art using routineexperimentation. Furthermore, the exact “effective” amount of the localanesthetic agent incorporated into a composition or dosage form of theinvention is not critical, so long as the concentration is within arange sufficient to permit ready application of the formulation so as todeliver an amount of the agent that is within a therapeuticallyeffective range.

[0022] “Effective amount” or “an effective permeation enhancing amount”of a permeation enhancer refers to a nontoxic, non-damaging butsufficient amount of the enhancer composition to provide the desiredincrease in skin permeability and, correspondingly, the desired depth ofpenetration, rate of administration, and amount of local anestheticagent delivered.

[0023] “Penetration enhancement” or “permeation enhancement” as usedherein relates to an increase in the permeability of the skin or mucosaltissue to the local anesthetic agent, i.e., so that the rate at whichthe agent permeates therethrough (i.e., the “flux” of agent through thebody surface) is increased relative to the rate that would be obtainedin the absence of the permeation enhancer. The enhanced permeationeffected through the use of such enhancers can be observed by measuringthe rate of diffusion of drug through animal or human skin using, forexample a Franz diffusion apparatus as known in the art and as employedin the Examples herein.

[0024] “Predetermined area” of skin or mucosal tissue, refers to thearea of skin or mucosal tissue through which a drug-enhancer formulationis delivered, and is a defined area of intact unbroken living skin ormucosal tissue. That area will usually be in the range of about 5-200cm², more usually in the range of about 5-100 cm², preferably in therange of about 20-60 cm². However, it will be appreciated by thoseskilled in the art of drug delivery that the area of skin or mucosaltissue through which drug is administered may vary significantly,depending on patch configuration, dose, and the like.

[0025] “Topical administration” is used in its conventional sense tomean delivery of a local anesthetic agent to the skin or mucosa, as in,for example, the treatment of various skin disorders. Topicaladministration, in contrast to transdermal administration, provides alocal rather than a systemic effect. However, unless otherwise stated orimplied, the terms “topical drug administration” and “transdermal drugadministration” are used interchangeably.

[0026] “Transdermal” drug delivery is meant administration of a localanesthetic agent to the skin surface of an individual so that the drugpasses through the skin tissue and into the individual's blood stream,thereby providing a systemic effect. The term “transdermal” is intendedto include “transmucosal” drug administration, i.e., administration of adrug to the mucosal (e.g., sublingual, buccal, vaginal, rectal) surfaceof an individual so that the drug passes through the mucosal tissue andinto the individual's blood stream.

[0027] “Treating” and “treatment” as used herein refer to reduction inseverity and/or frequency of symptoms, elimination of symptoms and/orunderlying cause, prevention of the occurrence of symptoms and/or theirunderlying cause, and improvement or remediation of damage. The presentmethod of “treating” a patient, as the term is used herein, thusencompasses both prevention of a disorder in a predisposed individualand treatment of the disorder in a clinically symptomatic individual.

II. The Permeation Enhancers

[0028] The permeation enhancer of the invention is an inorganic or anorganic pharmaceutically acceptable base. Preferred inorganic basesinclude inorganic hydroxides, inorganic oxides, inorganic salts of weakacids, and combinations thereof. Preferred organic bases are nitrogenousbases.

[0029] It has long been thought that strong bases, such as NaOH, werenot suitable as permeation enhancers because they would damage skin. Ithas been now been discovered that the skin permeability of localanesthetic agents can be enhanced without skin damage by exposing theskin to a base or basic solution, in a skin contacting formulation orpatch. The desired pH of the solution on the skin can be obtained usinga variety of bases or base concentrations. Accordingly, the pH isselected so as to be low enough so as to not cause skin damage, but highenough to enhance skin permeation to various local anesthetic agents. Assuch, it is important that the amount of base in any patch orformulation is optimized so as to increase the flux of the agent throughthe body surface while minimizing any possibility of skin damage. Ingeneral, this means that the pH at the body surface in contact with aformulation or drug delivery system of the invention (i.e., theinterface between the body surface and the formulation or deliverysystem) is preferably in the range of approximately 8.0-13.0, preferablyabout 8.0-11.5, more preferably about 8.5 to 11.5 and most preferablyabout 8.5-10.5.

[0030] In one preferred embodiment, the pH at the interface is theprimary design consideration, i.e., the composition or system isdesigned so as to provide the desired pH at the interface. Anhydrousformulations and transdermal systems may not have a measurable pH, andthe formulation or system can be designed so as to provide a target pHat the interface. Moisture from the body surface can migrate into theformulation or system, dissolve the base and thus release the base intosolution, which will then provide the desired target pH at theinterface. In those instances, a hydrophilic composition is preferred.In addition, when using aqueous formulations, the pH of the formulationmay change over time after it is applied on the skin. For example, gels,solutions, ointments, etc., may experience a net loss of moisture afterbeing applied to the body surface, i.e., the amount of water lost isgreater than the amount of water received from the body surface. In thatcase, the pH of the formulation may be different than its pH whenmanufactured. This problem can be easily remedied by designing theaqueous formulations to provide a target pH at the interface.

[0031] In other embodiments of the invention, the pH of the formulationor the drug composition contained within a delivery system will be inthe range of approximately 8.0-13.0, preferably about 8.0-11.5, morepreferably about 8.5 to 11.5, and most preferably about 8.5-10.5. In oneembodiment of the invention the pH of the formulation is higher than thepH at the interface. For example, if an aqueous formulation is used,moisture from the body surface can dilute the formulation, and thusprovide for a different pH at the interface, which will typically belower than that of the formulation itself.

[0032] In one preferred embodiment, the body surface is exposed to abase or basic solution for a sufficient period of time so as to providea high pH at the skin surface, thus creating channels in the skin ormucosa for the drug to go through. It is expected that drug flux isproportional to the strength of the solution and the duration ofexposure. However, it is desirable to balance the maximization of drugflux with the minimization of skin damage. This can be done in numerousways. For example, the skin damage may be minimized by selecting a lowerpH within the 8.0-13.0 range, by exposing the skin to the formulation orsystem for a shorter period of time, or by including at least oneirritation-mitigating additive. Alternatively, the patient can beadvised to change the location of application with each subsequentadministration.

[0033] The methods and compositions of the invention are expected toprovide an enhanced flux of local anesthetic agents in the range of atleast about 1.5-fold, preferably at least about 3-fold, as compared tothe flux observed in the absence of the basic enhancers describedherein.

[0034] While certain preferred amounts are set forth below, it isunderstood that, for all of the inorganic and organic bases describedherein, the optimum amount of any such base will depend on the strengthor weakness of the base and its molecular weight, and other factors suchas the number of ionizable sites in the active agent being administeredand whether there are any acidic species present in the formulation orpatch. One skilled in the art may readily determine the optimum amountfor any particular base such that the degree of enhancement is optimizedwhile the possibility of damage to the body surface is eliminated or atleast substantially minimized.

[0035] A. Inorganic Base

[0036] Exemplary inorganic bases are inorganic hydroxides, inorganicoxides, inorganic salts of weak acids, and combinations thereof.Preferred inorganic bases are those whose aqueous solutions have a highpH, and are acceptable as food or pharmaceutical additives. Examples ofsuch preferred inorganic bases are those listed below, along with theirrespective pHs. Some of the bases are identified by their hydrate forms,and it is understood that when referring to a “base”, both the hydratedand non-hydrated forms are intended to be included. Inorganic base pH ofAqueous Solution (concentration) Ammonium hydroxide^(1, 2, 3) 11.27 (1N), 10.27 (0.001 N) Sodium hydroxide^(1, 2, 3) 14 (5%), 13 (0.5%), 12(0.05%) Potassium hydroxide^(1, 2, 3) 13.5 (0.1 M) Calcium^(1, 3) 12.4(saturated solution in water) Magnesium hydroxide^(1, 3) 9.5 to 10.5slurry

[0037] Inorganic base pH of Aqueous Solution (concentration) Magnesiumoxide^(1, 2, 3) 10.3 (saturated aqueous solution) Calcium oxide³ Solublein water, Form Ca(OH)₂ Sodium acetate^(1, 3) ˜8.9 (0.1 N) Sodiumacetate, trihydrate^(1, 2) 8.9 (0.1 N) Sodium acetate, anhydrous^(1, 2)˜8.9 (0.1 N) Sodium borate decahydrate^(1, 2) ˜8.8-9.4, 9.15 to 9.2(0.01 M) Sodium borate^(1, 2, 3) 8.8-9.4, 9.15 to 9.2 (0.01 M) Sodiummetaborate Strongly alkaline Sodium carbonate^(1, 2, 3) ˜11.6 Sodiumcarbonate hydrate¹ ˜11.6 Sodium carbonate anhydrous ˜11.6 Sodiumbicarbonate^(1, 2, 3) 8.3 (0.1 M fresh) Sodium phosphate,tribasic^(1, 3) ˜11.5 (0.1%), ˜11.7 (0.5%), ˜11.9 (1.0%) Sodiumphosphate, tribasic dodecahydrate 11.5 (0.1%), 11.7 (0.5%), 11.9 (1.0%)Sodium phosphate, dibasic, anhydrous^(1, 2) 9.1 (1%) Sodium phosphate,dibasic, heptahydrate^(1, 2) ˜9.5 Sodium phosphate, dibasic^(1, 3) ˜9.5Sodium phosphate, dibasic, dihydrate¹ ˜9.5 Sodium phosphate, dibasic,dodecahydrate ˜9.5 Potassium carbonate^(1, 3) ˜11.6 Potassiumbicarbonate³ 8.2 (0.1 M) Potassium citrate^(1, 2, 3) ˜8.5 Potassiumcitrate monohydrate ˜8.5 Potassium acetate^(1, 3) 9.7 (0.1 M) Potassiumphosphate, dibasic^(1, 2) Aqueous solution is slightly alkalinePotassium phosphate, tribasic³ Aqueous solution is strongly alkalineAmmonium phosphate, dibasic^(1, 2, 3) ˜8

Inorganic Hydroxides

[0038] Inorganic hydroxides include, for example, ammonium hydroxide,alkali metal hydroxide and alkaline earth metal hydroxides, and mixturesthereof. Preferred inorganic hydroxides include ammonium hydroxide;monovalent alkali metal hydroxides such as sodium hydroxide andpotassium hydroxide; divalent alkali earth metal hydroxides such ascalcium hydroxide and magnesium hydroxide; and combinations thereof

[0039] The amount of inorganic hydroxide included in the compositionsand systems of the invention, will typically represent about 0.5-4.0 wt%, preferably about 0.5-3.0 wt %, more preferably about 0.75-2.0 wt %,of a topically applied formulation or of a drug reservoir of a drugdelivery system, or patch.

[0040] The aforementioned amounts are particularly applicable to thoseformulations and patches in which the local anesthetic agent is (1) anuncharged molecule, e.g., wherein a basic drug is in nonionized,free-base form, (2) a basic salt of an acidic drug, or (3) there are noadditional species in the formulation or patch that could react with orbe neutralized by the inorganic hydroxide, to any significant degree.

[0041] For formulations and patches in which the agent is in the form ofan acid addition salt, and/or wherein there are additional species inthe formulations or systems that can be neutralized by or react with theinorganic base (i.e., acidic inactive ingredients), the amount ofinorganic hydroxide is preferably the total of (1) the amount necessaryto neutralize the acid addition salt and/or other base-neutralizablespecies (i.e., the “acidic species”), plus (2) about 0.5-4.0 wt %,preferably about 0.5-3.0 wt %, more preferably about 0.75-2.0 wt %, ofthe formulation or drug reservoir. That is, for an acid addition salt,the enhancer is preferably present in an amount just sufficient toneutralize the salt, plus an additional amount (i.e., about 0.5-4.0 wt%, preferably about 0.5-3.0 wt %, more preferably about 0.75-2.0 wt %)to enhance the flux of the drug through the skin or mucosal tissue.Basic drugs in the form of a neutral, free base or basic salt of acidicdrug are usually not affected by a base, and thus for these drugs, theamount in (1) is usually the amount necessary to neutralize inactivecomponents that are acidic. For patches, the aforementioned percentagesare given relative to the total weight of the formulation components andthe adhesive, gel or liquid reservoir.

[0042] Still greater amounts of inorganic hydroxide may be used bycontrolling the rate and/or quantity of release of the base, preferablyduring the drug delivery period itself.

Inorganic Oxides

[0043] Inorganic oxides include, for example, magnesium oxide, calciumoxide, and the like.

[0044] The amount of inorganic oxide included in the compositions andsystems of the invention may be substantially higher than the numbersset forth above for the inorganic hydroxide, and may be as high as 20 wt%, in some cases as high as 25 wt % or higher, but will generally be inthe range of about 2-20 wt %. These amounts may be adjusted to take intoconsideration the presence of any base-neutralizable species.

Inorganic Salts of Weak Acids

[0045] Inorganic salts of weak acids include, ammonium phosphate(dibasic); alkali metal salts of weak acids such as sodium acetate,sodium borate, sodium metaborate, sodium carbonate, sodium bicarbonate,sodium phosphate (tribasic), sodium phosphate (dibasic), potassiumcarbonate, potassium bicarbonate, potassium citrate, potassium acetate,potassium phosphate (dibasic), potassium phosphate (tribasic); alkalineearth metal salts of weak acids such as magnesium phosphate and calciumphosphate; and the like, and combinations thereof.

[0046] Preferred inorganic salts of weak acids include, ammoniumphosphate (dibasic) and alkali metal salts of weak acids.

[0047] The amount of inorganic salts of weak acids included in thecompositions and systems of the invention may be substantially higherthan the numbers set forth above for the inorganic hydroxide, and may beas high as 20 wt %, in some cases as high as 25 wt % or higher, but willgenerally be in the range of approximately 2-20 wt %. These amounts maybe adjusted to take into consideration the presence of anybase-neutralizable species.

B. Organic Bases

[0048] Organic bases suitable for use in the invention are compoundshaving an amino group, amido group, an oxime, a cyano group, an aromaticor non-aromatic nitrogen-containing heterocycle, a urea group, andcombinations thereof. More specifically, examples of suitable organicbases are nitrogenous bases, which include, but are not limited to,primary amines, secondary amines, tertiary amines, amides, oximes, cyano(—CN) containing groups, aromatic and non-aromatic nitrogen-containingheterocycles, urea, and mixtures thereof. Preferred organic bases areprimary amines, secondary amines, tertiary amines, aromatic andnon-aromatic nitrogen-containing heterocycles, and mixtures thereof.

[0049] For nitrogenous bases, the amount of enhancing agent willtypically represent about 0.5-4.0 wt %, preferably about 0.5-3.0 wt %,more preferably about 0.75-2.0 wt %, of a topically applied formulationor of a drug reservoir of a drug delivery system or a patch. Theseamounts may be adjusted to take into consideration the presence of anybase-neutralizable species.

[0050] Still greater amounts of the nitrogenous base may be useddepending on the strength of the base and the rate and/or quantity ofrelease of the nitrogenous base preferably during the drug deliveryperiod itself.

[0051] Preferred organic bases are those whose aqueous solutions have ahigh pH or a high pKa (more preferably a pKa>9), and are acceptable asfood or pharmaceutical additives. Examples of such preferred organicbases are those listed below, along with their respective pHs (or pKavalues). Organic base pH of Aqueous Solution (concentration)2-amino-2-methyl-1,3-propanediol¹ 10.8 (0.1 m)2-amino-2-methyl-1-propanol¹ 11.3 (0.1 m) Diethanolamine¹ 11.0 (0.1 N)Triethanolamine¹ 10.5 (0.1 N) Butylamine² pKa = 10.56 Dimethylamine²Strong base, pKa = 10.73 Cyclohexylamine² Strong base, pKa = 10.64Ethylenediamine² Strong base, pKa = 10.71 Isopentylamine² pKa = 10.6Monoethanolamine² 12.1 (25%), 12.05 (0.1 N), pKa = 9.4 Phenethylamine²Strong base, pKa = 9.83 Piperidine² Strong base, pKa = 11.12Pyrrolidine² Strong base, pKa = 11.27 Trimethylamine² Strong base, pKa =9.81

Amines

[0052] Amines are compounds that include at least one primary amino(—NH₂) group, mono-substituted (secondary) amino group or di-substituted(tertiary) amino group.

[0053] Primary amino groups, secondary amino groups, and tertiary aminogroups may be generically grouped as encompassed by the molecularstructure —NR¹R²R³ wherein R¹, R², and R³ may be the same or differentand are generally selected from the group consisting of H, alkyl,hydroxyalkyl, alkoxyalkyl, alkenyl, hydroxyalkenyl, alkoxyalkenyl,cycloalkyl, cycloalkyl-substituted alkyl, monocyclic aryl, andmonocyclic aryl-substituted alkyl, all of which may be substituted withone or more nonhydrocarbyl substituents, e.g., 1 to 3 halo, hydroxyl,thiol, or lower alkoxy groups.

[0054] Exemplary primary amines include 2-aminoethanol, 2-aminoheptane,2-amino-2-methyl-1,3 propanediol, 2-amino-2-methyl-1-propanol,n-amylamine, benzylamine, 1,4-butanediamine, n-butylamine,cyclohexylamine, ethylamine, ethylenediamine, methylamine,α-methylbenzylamine, phenethylamine, propylamine, andtris(hydroxymethyl)aminomethane.

[0055] Exemplary secondary amines include compounds that contain groupssuch as methylamino, ethylamino, isopropylamino, butylamino,cyclopropylamino, cyclohexylamino, n-hexylamino, phenylamino,benzylamino, chloroethylamino, hydroxyethylamino, and so forth.Exemplary secondary amines include diethanolamine, diethylamine,diisopropylamine, and dimethylamine.

[0056] Exemplary tertiary amines include compounds that contain groupssuch as dibutylamino, diethylamino, dimethylamino, diisopropylamino,ethylchloroethylamino, ethylcyclopropylamino, methylhexylamino,methylcyclohexylamino, methylpropylamino, methylbenzylamino,methyl-p-chlorophenylamino, methylcyclohexylamino, methylphenylamino,methyltoluylamino, and so forth. Exemplary tertiary amines includeN,N-diethylaniline, N,N-dimethylglycine, triethanolamine, triethylamine,and trimethylamine.

Amides

[0057] Amides are compounds that include an amido group that has themolecular structure —(CO)—NR¹R² where R¹ and R² can be the same ordifferent, and are generally selected from the groups consisting of H,alkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, hydroxyalkenyl,alkoxyalkenyl, cycloalkyl, cycloalkyl-substituted alkyl, monocyclicaryl, and monocyclic aryl-substituted alkyl, all of which may besubstituted with one or more nonhydrocarbyl substituents, e.g., 1 to 3halo, hydroxyl, thiol, or lower alkoxy groups.

Aromatic Nitrogen-Containing Heterocycles

[0058] Aromatic nitrogen-containing heterocycles, typically contain a 5-or 6-membered monocyclic substituent, or a bicyclic fused or linked 5-or 6-membered ring, such as imidazolyl, indolyl, pyridinyl, pyrimidinyl,pyrrolyl, quinolinyl, tetrazolyl, 1,2,4-triazolyl, etc.

[0059] Aromatic nitrogen-containing heterocycles suitable as the organicbase herein include, by way of example, 2-amino-pyridine, benzimidazole,2,5-diaminopyridine, 2,4-dimethylimidazole, 2,3-dimethylpyridine,2,4-dimethylpyridine, 3,5-dimethylpyridine, imidazole, methoxypyridine,γ-picoline, 2,4,6-trimethylpyridine, and combinations thereof.

Non-Aromatic Nitrogen-Containing Heterocycles

[0060] Non-aromatic nitrogen-containing heterocycles, typically contain4- to 6-membered rings such as acetimido, morpholinyl, lactams andimides (e.g., γ-butyrolactam, ε-caprolactam, N-phenyl-β-propiolactam),phthalimido, piperidyl, piperidino, piperazinyl, pyrrolidinyl,succinimido, etc.

[0061] Non-aromatic nitrogen-containing heterocycles include, by way ofexample, 1,2-dimethylpiperidine, 2,5-dimethylpiperazine,1,2-dimethylpyrrolidine, 1-ethylpiperidine, n-methylpyrrolidine,morpholine, piperazine, piperidine, pyrrolidine,2,2,6,6-tetramethylpiperidine, 2,2,4-trimethylpiperidine, andcombinations thereof.

III. The Active Agent

[0062] The active agent administered may be any local anesthetic agentthat is suitable for topical, transdermal or transmucosal delivery(e.g., can be delivered through body surfaces and membranes, includingskin) and induces the desired local or systemic effect. Exemplary usesfor such agents include, by way of example and not limitation, treatmentfor burns, contact dermatitis, insect bites, pain, pruritus, skin rash,wounds, and so forth.

[0063] Exemplary local anesthetics that may be administered using themethods, compositions and systems of the invention include, but are notlimited to, alcohols such as phenol; benzyl benzoate; calamine;chloroxylenol; dyclonine; ketamine; menthol; pramoxine; resorcinol;troclosan; and procaine drugs such as benzocaine, bupivacaine,chloroprocaine, cinchocaine, cocaine, dexivacaine, diamocaine,dibucaine, etidocaine, hexylcaine, levobupivacaine, lidocaine,mepivacaine, oxethazaine, prilocaine, procaine, proparacaine,propoxycaine, pyrrocaine, risocaine, rodocaine, ropivacaine, andtetracaine; and pharmaceutically acceptable derivatives thereof, andcombinations thereof

[0064] Derivatives of these compounds, such as pharmaceuticallyacceptable salts and esters are also of particular interest, forexample, bupivacaine HCl, chloroprocaine HCl, diamocaine cyclamate,dibucaine HCl, dyclonine HCl, etidocaine HCl, levobupivacaine HCl,lidocaine HCl, mepivacaine HCl, pramoxine HCl, prilocaine HCl, procaineHCl, proparacaine HCl, propoxycaine HCl, ropivacaine HCl, tetracaineHCl, and so forth, and so forth.

[0065] Preferred local anesthetics include bupivacaine, chloroprocaine,dibucaine, etidocaine, levobupivacaine, lidocaine, mepivacaine,prilocaine, ropivacaine, tetracaine, and pharmaceutically acceptablesalts and esters thereof.

[0066] The local anesthetic agent may be administered, if desired, inthe form of a salt, ester, amide, prodrug, derivative, or the like,provided the salt, ester, amide, prodrug or derivative is suitablepharmacologically. Salts, esters, amides, prodrugs and other derivativesof local anesthetic agents may be prepared using standard proceduresknown to those skilled in the art of synthetic organic chemistry anddescribed, for example, by March's Advanced Organic Chemistry:Reactions, Mechanisms and Structure, 5th Ed. (Wiley-Interscience, 2001).

[0067] For example, acid addition salts are prepared from the free base(e.g., an amine drug) using conventional methodology, by reaction with asuitable acid. Generally, the base form of the drug is dissolved in apolar organic solvent such as methanol or ethanol and the acid is addedthereto. The resulting salt either precipitates or may be brought out ofsolution by addition of a less polar solvent. Suitable acids forpreparing acid addition salts include both organic acids, e.g., aceticacid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malicacid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaricacid, citric acid, benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,salicylic acid, and the like, as well as inorganic acids, e.g.,hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like. An acid addition salt may be reconvertedto the free base by treatment with a suitable base. Particularlypreferred acid addition salts of the active agents herein are halidesalts, such as may be prepared using hydrochloric or hydrobromic acids.

[0068] Preparation of basic salts of acids are prepared in a similarmanner using a pharmaceutically acceptable base such as sodiumhydroxide, potassium hydroxide, ammonium hydroxide, calcium hydroxide,trimethylamine, or the like. Particularly preferred basic salts hereinare alkali metal salts, e.g., the sodium salt, and copper salts.

[0069] Preparation of esters involves functionalization of hydroxyland/or carboxyl groups that may be present within the molecularstructure of the drug. The esters are typically acyl-substitutedderivatives of free alcohol groups, i.e., moieties that are derived fromcarboxylic acids of the formula RCOOH where R is alkyl, and preferablyis lower alkyl. Esters can be reconverted to the free acids, if desired,by using conventional hydrogenolysis or hydrolysis procedures. Amidesand prodrugs may also be prepared using techniques known to thoseskilled in the art or described in the pertinent literature. Forexample, amides may be prepared from esters, using suitable aminereactants, or they may be prepared from an anhydride or an acid chlorideby reaction with ammonia or a lower alkyl amine. Prodrugs are typicallyprepared by covalent attachment of a moiety, which results in a compoundthat is therapeutically inactive until modified by an individual'smetabolic system.

[0070] For those local anesthetic agents that may be chiral in natureand can thus be in an enantiomerically pure form or in a racemicmixture, the drug may be incorporated into the present dosage unitseither as the racemate or in the enantiomerically pure form.

[0071] The amount of local anesthetic agent administered will depend ona number of factors and will vary from subject to subject and depend onthe particular agent administered, the particular disorder or conditionbeing treated, the severity of the symptoms, the subject's age, weightand general condition, and the judgment of the prescribing physician. Inparticular, due to differences in systemic absorption and toxicity, theconcentration of the drug used depends on the condition being treated orthe anesthetic procedure the patient may be undergoing.

[0072] Other factors, specific to transdermal drug delivery, include thesolubility and permeability of the carrier and adhesive layer in a drugdelivery device, if one is used, and the period of time for which such adevice will be fixed to the skin or other body surface. The minimumamount of local anesthetic agent is determined by the requirement thatsufficient quantities of drug must be present in a device or compositionto maintain the desired rate of release over the given period ofapplication. The maximum amount for safety purposes is determined by therequirement that the quantity of drug present cannot exceed a rate ofrelease that reaches toxic levels. Generally, the maximum concentrationis determined by the amount of agent that can be received in the carrierwithout producing adverse histological effects such as irritation, anunacceptably high initial pulse of agent into the body, or adverseeffects on the characteristics of the delivery device such as the lossof tackiness, viscosity, or deterioration of other properties.

IV. Pharmaceutical Formulations

[0073] One embodiment of the invention is a composition for the enhanceddelivery of a local anesthetic agent through a body surface, comprisinga formulation of: (a) a therapeutically effective amount of the drug;(b) a pharmaceutically acceptable inorganic or organic base in an amounteffective to provide a pH within the range of about 8.0-13.0 at thelocalized region of the body surface during administration of the agentand to enhance the flux of the agent through the body surface withoutcausing damage thereto; and (c) a pharmaceutically acceptable carriersuitable for topical or transdermal drug administration. The formulationis typically, but not necessarily, an aqueous formulation. The pH ismore preferably about 8.0-11.5, and most preferably about 8.5-10.5.

[0074] Accordingly, while the method of delivery of the active agent mayvary, the method will typically involve application of a formulation ordrug delivery system containing a pharmaceutically acceptable inorganicor organic base to a predetermined area of the skin or other tissue fora period of time sufficient to provide the desired local or systemiceffect. The method may involve direct application of the composition asan ointment, gel, cream, or the like, or may involve use of a drugdelivery device. In either case, water is preferably present in orderfor the hydroxide ions to be provided by the base, and thus enhance theflux of the active agent through the patient's body surface. Thus, sucha formulation or drug reservoir may be aqueous, i.e., contain water, ormay be nonaqueous and used in combination with an occlusive backing sothat moisture evaporating from the body surface is maintained within theformulation or transdermal system during drug administration. In somecases, however, e.g., with an occlusive gel, a nonaqueous formulationmay be used with or without an occlusive backing layer.

[0075] Suitable formulations include ointments, creams, gels, lotions,solutions, pastes, and the like. Ointments, as is well known in the artof pharmaceutical formulation, are semisolid preparations that aretypically based on petrolatum or other petroleum derivatives. Thespecific ointment foundation to be used, as will be appreciated by thoseskilled in the art, is one that will provide for optimum drug delivery,and, preferably, will provide for other desired characteristics as well,e.g., emolliency or the like. As with other carriers or vehicles, anointment foundation should be inert, stable, nonirritating andnonsensitizing. As explained in Remington: The Science and Practice ofPharmacy, 20^(th) edition (Lippincott Williams & Wilkins, 2000),ointment foundations may be grouped in four classes: oleaginous,emulsifiable, emulsion, and water-soluble. Oleaginous ointmentfoundations include, for example, vegetable oils, fats obtained fromanimals, and semisolid hydrocarbons obtained from petroleum.Emulsifiable ointment foundations, also known as absorbent ointmentfoundations, contain little or no water and include, for example,hydroxystearin sulfate, anhydrous lanolin and hydrophilic petrolatum.Emulsion ointment foundations are either water-in-oil (W/O) emulsions oroil-in-water (O/W) emulsions, and include, for example, cetyl alcohol,glyceryl monostearate, lanolin and stearic acid. Preferred water-solubleointment foundations are prepared from polyethylene glycols of varyingmolecular weight.

[0076] Creams, as also well known in the art, are viscous liquids orsemisolid emulsions, either oil-in-water or water-in-oil. Creamfoundations are water-washable, and contain an oil phase, an emulsifierand an aqueous phase. The oil phase, also called the “internal” phase,is generally comprised of petrolatum and a fatty alcohol such as cetylor stearyl alcohol. The aqueous phase usually, although not necessarily,exceeds the oil phase in volume, and generally contains a humectant. Theemulsifier in a cream formulation is generally a nonionic, anionic,cationic or amphoteric surfactant.

[0077] As will be appreciated by those working in the field ofpharmaceutical formulation, gels are semisolid, suspension-type systems.Single-phase gels contain organic macromolecules distributedsubstantially uniformly throughout the carrier liquid, which istypically aqueous, but also, preferably, contain an alcohol and,optionally, an oil. Preferred organic macromolecules, i.e., gellingagents, are crosslinked acrylic acid polymers such as the “carbomer”family of polymers, e.g., carboxypolyalkylenes that may be obtainedcommercially under the Carbopol® trademark. Also preferred arehydrophilic polymers such as polyethylene oxides,polyoxyethylene-polyoxypropylene copolymers and polyvinylalcohol;cellulosic polymers such as hydroxypropyl cellulose, hydroxyethylcellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulosephthalate, and methyl cellulose; gums such as tragacanth and xanthangum; sodium alginate; and gelatin. In order to prepare a uniform gel,dispersing agents such as alcohol or glycerin can be added, or thegelling agent can be dispersed by trituration, mechanical mixing orstirring, or combinations thereof.

[0078] Lotions, which are preferred for delivery of cosmetic agents, arepreparations to be applied to the skin surface without friction, and aretypically liquid or semiliquid preparations in which solid particles,including the active agent, are present in a water or alcohol base.Lotions are usually suspensions of solids, and preferably, for thepresent purpose, comprise a liquid oily emulsion of the oil-in-watertype. Lotions are preferred formulations herein for treating large bodyareas, because of the ease of applying a more fluid composition. It isgenerally necessary that the insoluble matter in a lotion be finelydivided. Lotions will typically contain suspending agents to producebetter dispersions as well as compounds useful for localizing andholding the active agent in contact with the skin, e.g.,methylcellulose, sodium carboxymethyl-cellulose, or the like.

[0079] Solutions are homogeneous mixtures prepared by dissolving one ormore chemical substances (solute) in another liquid such that themolecules of the dissolved substance are dispersed among those of thesolvent. The solution may contain other pharmaceutically acceptablechemicals to buffer, stabilize or preserve the solute. Commonly usedexamples of solvents used in preparing solutions are ethanol, water,propylene glycol or any other pharmaceutically acceptable vehicle.

[0080] Pastes are semisolid dosage forms in which the active agent issuspended in a suitable foundation. Depending on the nature of thefoundation, pastes are divided between fatty pastes or those made fromsingle-phase, aqueous gels. The foundation in a fatty paste is generallypetrolatum or hydrophilic petrolatum or the like. The pastes made fromsingle-phase aqueous gels generally incorporate carboxymethylcelluloseor the like as the foundation.

[0081] Formulations may also be prepared with liposomes, micelles, andmicrospheres. Liposomes are microscopic vesicles having a lipid wallcomprising a lipid bilayer, and can be used as drug delivery systemsherein as well. Generally, liposome formulations are preferred forpoorly soluble or insoluble pharmaceutical agents. Liposomalpreparations for use in the instant invention include cationic(positively charged), anionic (negatively charged) and neutralpreparations. Cationic liposomes are readily available. For example,N-[1-2,3-dioleyloxy)propyl]-N,N,N-triethylammonium liposomes areavailable under the tradename Lipofectin® (GIBCO BRL, Grand Island,N.Y.). Anionic and neutral liposomes are readily available as well,e.g., from Avanti Polar Lipids (Birmingham, Ala.), or can be easilyprepared using readily available materials. Such materials includephosphatidyl choline, cholesterol, phosphatidyl ethanolamine,dioleoylphosphatidyl choline, dioleoylphosphatidyl glycerol,dioleoylphoshatidyl ethanolamine, among others. These materials can alsobe mixed with N-[1-2,3-dioleyloxy)propyl]-N,N,N-triethylammonium (DOTMA)in appropriate ratios. Methods for making liposomes using thesematerials are well known in the art.

[0082] Micelles are known in the art and are comprised of surfactantmolecules arranged so that their polar headgroups form an outerspherical shell, while the hydrophobic, hydrocarbon chains are orientedtowards the center of the sphere, forming a core. Micelles form in anaqueous solution containing surfactant at a high enough concentration sothat micelles naturally result. Surfactants useful for forming micellesinclude, but are not limited to, potassium laurate, sodium octanesulfonate, sodium decane sulfonate, sodium dodecane sulfonate, sodiumlauryl sulfate, docusate sodium, decyltrimethylammonium bromide,dodecyltrimethylammonium bromide, tetradecyltrimethylammonium bromide,tetradecyltrimethyl-ammonium chloride, dodecylammonium chloride,polyoxyl 8 dodecyl ether, polyoxyl 12 dodecyl ether, nonoxynol 10 andnonoxynol 30. Micelle formulations can be used in conjunction with thepresent invention either by incorporation into the reservoir of atopical or transdermal delivery system, or into a formulation to beapplied to the body surface.

[0083] Microspheres, similarly, may be incorporated into the presentformulations and drug delivery systems. Like liposomes and micelles,microspheres essentially encapsulate a drug or drug-containingformulation. They are generally, although not necessarily, formed fromlipids, preferably charged lipids such as phospholipids. Preparation oflipidic microspheres is well known in the art and described in thepertinent texts and literature.

[0084] Various additives, known to those skilled in the art, may beincluded in the topical formulations. For example, solvents, includingrelatively small amounts of alcohol, may be used to solubilize certaindrug substances. Other optional additives include opacifiers,antioxidants, fragrance, colorant, gelling agents, thickening agents,stabilizers, surfactants and the like. Other agents may also be added,such as antimicrobial agents, to prevent spoilage upon storage, i.e., toinhibit growth of microbes such as yeasts and molds. Suitableantimicrobial agents are typically selected from the group consisting ofthe methyl and propyl esters of p-hydroxybenzoic acid (i.e., methyl andpropyl paraben), sodium benzoate, sorbic acid, imidurea, andcombinations thereof.

[0085] For those local anesthetic agents having an unusually low rate ofpermeation through the skin or mucosal tissue, it may be desirable toinclude a second permeation enhancer in the formulation in addition tothe inorganic or organic base enhancer, although in a preferredembodiment the base enhancer is administered without any otherpermeation enhancers. Any other enhancers should, like the baseenhancer, minimize the possibility of skin damage, irritation, andsystemic toxicity. Examples of classes of suitable secondary enhancers(or “co-enhancers”) include, but are not limited to, fatty acids, bothsaturated and unsaturated; fatty alcohols; bile acids; nonionicsurfactants, including esters of fatty acids, fatty (long-chain alkyl oralkenyl) esters of monohydric alcohols, diols, and polyols, diols andpolyols that are both esterified with a fatty acid and substituted witha polyoxyalkylene, polyoxyalkylene fatty acid esters, polyoxyalkylenefatty ethers, polyoxyalkylene fatty ethers, and polyglyceryl fatty acidesters; amines; amides; N-alkyl-azacycloalkanones andN-alkyl-azacycloalkenones; hydrocarbon solvents; terpenes; lower alkylesters; cyclodextrin enhancers; nitrogen-containing heterocycles;sulfoxides; and urea and its derivatives.

[0086] Specific examples of suitable co-enhancers include ethers such asdiethylene glycol monoethyl ether (available commercially asTranscutol®, Gattefosse SA) and diethylene glycol monomethyl ether;surfactants such as sodium laurate, sodium lauryl sulfate,cetyltrimethylammonium bromide, benzalkonium chloride, Poloxamer (231,182, 184), Tween (20, 40, 60, 80) and lecithin; alcohols such asethanol, propanol, octanol, benzyl alcohol, and the like; fatty acidssuch as lauric acid, oleic acid and valeric acid; fatty acid esters suchas isopropyl myristate, isopropyl palmitate, methylpropionate, and ethyloleate; polyols and esters thereof such as polyethylene glycol, andpolyethylene glycol monolaurate; amides and other nitrogenous compoundssuch as urea, dimethylacetamide, dimethylformamide, 2-pyrrolidone,1-methyl-2-pyrrolidone, ethanolamine, diethanolamine andtriethanolamine; terpenes; alkanones; and organic acids, particularlycitric acid and succinic acid. Azone® and sulfoxides such asdimethylsulfoxide and decylmethylsulfoxide may also be used, but areless preferred. Percutaneous Penetration Enhancers, eds. Smith et al.(CRC Press, 1995) provides an excellent overview of the field andfurther information concerning possible secondary enhancers for use inconjunction with the present invention.

[0087] The formulation may also contain irritation-mitigating additivesto minimize or eliminate the possibility of skin irritation or skindamage resulting from the local anesthetic agent, the base enhancer, orother components of the formulation. Suitable irritation-mitigatingadditives include, for example: α-tocopherol; monoamine oxidaseinhibitors, particularly phenyl alcohols such as 2-phenyl-1-ethanol;glycerin; salicylic acids and salicylates; ascorbic acids andascorbates; ionophores such as monensin; amphiphilic amines; ammoniumchloride; N-acetylcysteine; cis-urocanic acid; capsaicin; andchloroquine. The irritant-mitigating additive, if present, may beincorporated into the formulation at a concentration effective tomitigate irritation or skin damage, typically representing not more thanabout 20 wt %, more typically not more than about 5 wt %, of theformulation.

[0088] The concentration of the local anesthetic agent in theformulation will typically depend upon a variety of factors, includingthe disease or condition to be treated, the nature and activity of theagent, the desired effect, possible adverse reactions, the ability andspeed of the agent to reach its intended target, and other factorswithin the particular knowledge of the patient and physician. Preferredformulations will typically contain on the order of about 0.5-50 wt %,preferably about 5-30 wt %, active agent.

V. Drug Delivery Systems

[0089] An alternative and preferred method involves the use of a drugdelivery system, e.g., a topical or transdermal “patch,” wherein thelocal anesthetic agent is contained within a laminated structure that isto be affixed to the skin. In such a structure, the drug composition iscontained in a layer, or “reservoir,” underlying an upper backing layerthat serves as the outer surface of the device during use. The laminatedstructure may contain a single reservoir, or it may contain multiplereservoirs.

[0090] Accordingly, another embodiment of the invention is a system forthe enhanced topical or transdermal administration of a local anestheticagent, comprising: (a) at least one drug reservoir containing the localanesthetic agent and a pharmaceutically acceptable inorganic or organicbase in an amount effective to enhance the flux of the local anestheticagent through the body surface without causing damage thereto; (b) ameans for maintaining the system in agent and base transmittingrelationship to the body surface and forming a body surface-systeminterface; and (c) a backing layer that serves as the outer surface ofthe device during use, wherein the base is effective to provide a pHwithin the range of about 8.0-13.0 at the body surface-system interfaceduring administration of the drug. The pH is more preferably about8.0-11.5, and most preferably about 8.5-10.5.

[0091] In one embodiment, the drug reservoir comprises a polymericmatrix of a pharmaceutically acceptable adhesive material that serves toaffix the system to the skin during drug delivery; typically, theadhesive material is a pressure-sensitive adhesive (PSA) that issuitable for long-term skin contact, and which should be physically andchemically compatible with the active agent, inorganic or organic base,and any carriers, vehicles or other additives that are present. Examplesof suitable adhesive materials include, but are not limited to, thefollowing: polyethylenes; polysiloxanes; polyisobutylenes;polyacrylates; polyacrylamides; polyurethanes; plasticizedethylene-vinyl acetate copolymers; and tacky rubbers such aspolyisobutene, polybutadiene, polystyrene-isoprene copolymers,polystyrene-butadiene copolymers, and neoprene (polychloroprene).Preferred adhesives are polyisobutylenes.

[0092] The backing layer functions as the primary structural element ofthe transdermal system and provides the device with flexibility and,preferably, occlusivity. The material used for the backing layer shouldbe inert and incapable of absorbing the local anesthetic agent, the baseenhancer, or other components of the formulation contained within thedevice. The backing is preferably comprised of a flexible elastomericmaterial that serves as a protective covering to prevent loss of drugand/or vehicle via transmission through the upper surface of the patch,and will preferably impart a degree of occlusivity to the system, suchthat the area of the body surface covered by the patch becomes hydratedduring use. The material used for the backing layer should permit thedevice to follow the contours of the skin and be worn comfortably onareas of skin such as at joints or other points of flexure, that arenormally subjected to mechanical strain with little or no likelihood ofthe device disengaging from the skin due to differences in theflexibility or resiliency of the skin and the device. The materials usedas the backing layer are either occlusive or permeable, as noted above,although occlusive backings are preferred, and are generally derivedfrom synthetic polymers (e.g., polyester, polyethylene, polypropylene,polyurethane, polyvinylidine chloride, and polyether amide), naturalpolymers (e.g., cellulosic materials), or macroporous woven and nonwovenmaterials.

[0093] During storage and prior to use, the laminated structurepreferably includes a release liner. Immediately prior to use, thislayer is removed from the device so that the system may be affixed tothe skin. The release liner should be made from a drug/vehicleimpermeable material, and is a disposable element, which serves only toprotect the device prior to application. Typically, the release liner isformed from a material impermeable to the local anesthetic agent and thebase enhancer, and which is easily stripped from the transdermal patchprior to use.

[0094] In an alternative embodiment, the drug-containing reservoir andskin contact adhesive are present as separate and distinct layers, withthe adhesive underlying the reservoir. In such a case, the reservoir maybe a polymeric matrix as described above. Alternatively, the reservoirmay be comprised of a liquid or semisolid formulation contained in aclosed compartment or pouch, or it may be a hydrogel reservoir, or maytake some other form. Hydrogel reservoirs are particularly preferredherein. As will be appreciated by those skilled in the art, hydrogelsare macromolecular networks that absorb water and thus swell but do notdissolve in water. That is, hydrogels contain hydrophilic functionalgroups that provide for water absorption, but the hydrogels arecomprised of crosslinked polymers that give rise to aqueousinsolubility. Generally, then, hydrogels are comprised of crosslinkedhydrophilic polymers such as a polyurethane, a polyvinyl alcohol, apolyacrylic acid, a polyoxyethylene, a polyvinylpyrrolidone, apoly(hydroxyethyl methacrylate) (poly(HEMA)), or a copolymer or mixturethereof. Particularly preferred hydrophilic polymers are copolymers ofHEMA and polyvinylpyrrolidone.

[0095] Additional layers, e.g., intermediate fabric layers and/orrate-controlling membranes, may also be present in any of these drugdelivery systems. Fabric layers may be used to facilitate fabrication ofthe device, while a rate-controlling membrane may be used to control therate at which a component permeates out of the device. The component maybe a drug, a base enhancer, an additional enhancer, or some othercomponent contained in the drug delivery system.

[0096] A rate-controlling membrane, if present, will be included in thesystem on the skin side of one or more of the drug reservoirs. Thematerial used to form such a membrane is selected so as to limit theflux of one or more components contained in the drug formulation.Representative materials useful for forming rate-controlling membranesinclude polyolefins such as polyethylene and polypropylene, polyamides,polyesters, ethylene-ethacrylate copolymer, ethylene-vinyl acetatecopolymer, ethylene-vinyl methylacetate copolymer, ethylene-vinylethylacetate copolymer, ethylene-vinyl propylacetate copolymer,polyisoprene, polyacrylonitrile, ethylene-propylene copolymer, and thelike.

[0097] Generally, the underlying surface of the transdermal device,i.e., the skin contact area, has an area in the range of about 5-200cm², preferably 5-100 cm², more preferably 20-60 cm². That area willvary, of course, with the amount of local anesthetic agent to bedelivered and the flux of the agent through the body surface. Largerpatches can be used to accommodate larger quantities of drug, whilesmaller patches can be used for smaller quantities of drug and/or drugsthat exhibit a relatively high permeation rate.

[0098] Such drug delivery systems may be fabricated using conventionalcoating and laminating techniques known in the art. For example,adhesive matrix systems can be prepared by casting a fluid admixture ofadhesive, local anesthetic agent and vehicle onto the backing layer,followed by lamination of the release liner. Similarly, the adhesivemixture may be cast onto the release liner, followed by lamination ofthe backing layer. Alternatively, the drug reservoir may be prepared inthe absence of drug or excipient, and then loaded by soaking in adrug/vehicle mixture. In general, transdermal systems of the inventionare fabricated by solvent evaporation, film casting, melt extrusion,thin film lamination, die cutting, or the like. The inorganic or organicbase permeation enhancer will generally be incorporated into the deviceduring patch manufacture rather than subsequent to preparation of thedevice. Thus, for acid addition salts of basic drugs (e.g.,hydrochloride salts of amine drugs), the enhancer will neutralize thedrug during manufacture of the drug delivery system, resulting in afinal drug delivery system in which the drug is present in nonionized,neutral form along with an excess of base to serve as a permeationenhancer. For nonionized acidic drugs, the base will neutralize suchdrugs by converting them to the ionized drug in salt form.

[0099] In a preferred delivery system, an adhesive overlayer that alsoserves as a backing for the delivery system is used to better secure thepatch to the body surface. This overlayer is sized such that it extendsbeyond the drug reservoir so that adhesive on the overlayer comes intocontact with the body surface. The overlayer is useful because theadhesive/drug reservoir layer may lose its adhesion a few hours afterapplication due to hydration. By incorporating such an adhesiveoverlayer, the delivery system will remain in place for the requiredperiod of time.

[0100] Other types and configurations of transdermal drug deliverysystems may also be used in conjunction with the method of the presentinvention, as will be appreciated by those skilled in the art oftransdermal drug delivery. See, for example, Ghosh, Transdermal andTopical Drug Delivery Systems (Interpharm Press, 1997), particularlyChapters 2 and 8.

[0101] As with the topically applied formulations of the invention, thelocal anesthetic agent and enhancer composition contained within thedrug reservoir(s) of these laminated systems may comprise a number ofadditional components. In some cases, the drug and enhancer may bedelivered neat, i.e., in the absence of additional liquid. In mostcases, however, the drug will be dissolved, dispersed or suspended in asuitable pharmaceutically acceptable vehicle, typically a solvent orgel. Other components that may be present include preservatives,stabilizers, surfactants, solubilizers, additional enhancers, and thelike.

[0102] The invention accordingly provides a novel and highly effectivemeans for increasing the flux of a local anesthetic agent through thebody surface (skin or mucosal tissue) of a human or animal. The baseenhancers discussed herein, employed in specific amounts relative to aformulation or drug reservoir, may be used as permeation enhancers witha wide variety of local anesthetic agents, including free acids, freebases, acid addition salts of basic drugs, basic addition salts ofacidic drugs, nonionizable drugs, peptides and proteins. Surprisingly,the increase in permeation is not accompanied by any noticeable tissuedamage, irritation, or sensitization. The invention thus represents animportant advance in the field of drug delivery.

[0103] It is to be understood that while the invention has beendescribed in conjunction with the preferred specific embodimentsthereof, the foregoing description is intended to illustrate and notlimit the scope of the invention. Other aspects, advantages andmodifications will be apparent to those skilled in the art to which theinvention pertains. Furthermore, the practice of the present inventionwill employ, unless otherwise indicated, conventional techniques of drugformulation, particularly topical and transdermal drug formulation,which are within the skill of the art. Such techniques are fullyexplained in the literature. See Remington: The Science and Practice ofpharmacy, cited supra, as well as Goodman & Gilman's The PharmacologicalBasis of Therapeutics, 10^(th) Ed.(2001).

[0104] The following examples are put forth so as to provide those ofordinary skill in the art with a complete disclosure and description ofhow to practice the methods as well as make and use the compositions ofthe invention, and are not intended to limit the scope of what theinventors regard as their invention. Efforts have been made to ensureaccuracy with respect to numbers (e.g., amounts, temperature, etc.) butsome errors and deviations should be accounted for. Unless indicatedotherwise, parts are parts by weight, temperature is in ° C. andpressure is at or near atmospheric. The following abbreviations will beused in accordance with the definitions set out below.

EXAMPLES Abbreviations

[0105] PG Propylene glycol

[0106] PIB Polyisobutylene

METHODS Preparation of Round Disc Samples

[0107] Each formulation was coated onto a release liner and dried in anoven at 65° C. for two hours to remove water and other solvents. Thedried drug-in-adhesive/release liner film was laminated to a backingfilm. The backing/drug-in-adhesive/release liner laminate was then cutinto round discs with a diameter of 9/16 inch.

Measurement of Permeation of Drugs Through Human Cadaver Skin

[0108] The in vitro permeation of drugs through human cadaver skin wasperformed using Franz-type diffusion cells with a diffusion area of 1cm². The volume of receiver solution was 8 ml. Human cadaver skin wascut to a proper size and placed on a flat surface with the stratumcorneum side facing up. The release liner was peeled away from the disclaminate. The backing/drug-in-adhesive film was placed and pressed onthe skin with the adhesive side facing the stratum corneum. Theskin/adhesive/backing laminate was clamped between the donor andreceiver chambers of the diffusion cell with the skin side facing thereceiver solution.

Measurement of pH

[0109] The pH of the patches was measured using the followingprocedures. A 2.4 cm² circular patch was punched out. Ten ml purifiedwater was pipetted into a glass vial, and a stir bar was added. Theliner was removed from the patch and placed in the vial along with thepatch. The vial was then placed on a stir plate and thewater/patch/liner mixture was stirred for 5 minutes, at which point theliner was removed from the vial and discarded. The vial was again placedon a stir plate and stirring continued for an additional 18 hours. After18 hours, the stir bar was removed from the vial and the pH of thesolution determined using a calibrated pH meter.

EXAMPLE 1

[0110] An in-vitro skin permeation study was conducted using threelidocaine transdermal systems, designated, Lido-1, Lido-2, Lido-3, thecompositions of which are set forth in Table 1. Round disc samples wereprepared as described in the Methods section. The theoretical percentweight for each ingredient after drying (calculated assuming all thevolatile ingredients were completely removed during drying) is listed inTable 2. TABLE 1 Component Weight and Weight Percent Based on TotalSolution Weight Lido-1 Lido-2 Lido-3 g (wt %) g (wt %) g (wt %)Lidocaine 0.50 (9.1) 0.50 (8.9) 0.50 (8.8) PG 0.50 (9.1) 0.50 (8.9) 0.50(8.8) Water 0 0.07 (1.2) 0.11 (1.8) PIB adhesive 4.00 (72.7) 4.00 (70.9)4.00 (70.1) (30% solid) NaOH 0 0.07 (1.2) 0.11 (1.8) n-Heptane 0.50(9.1) 0.50 (8.9) 0.50 (8.8)

[0111] TABLE 2 Component Weight and Weight Percent Based on Dried FilmWeight Lido-1 Lido-2 Lido-3 g (wt %) g (wt %) g (wt %) Lidocaine 0.50(22.7) 0.50 (22.0) 0.50 (21.7) PG 0.50 (22.7) 0.50 (22.0) 0.50 (21.7)PIB adhesive 1.20 (54.4) 1.20 (52.9) 1.20 (52.1) NaOH 0 0.07 (3.1) 0.11(4.6)

[0112] Since the reaction between lidocaine and NaOH is not expected tobe significant, the concentration of NaOH in the system is assumed to beindependent from the amount of lidocaine added. Therefore, the NaOHconcentration listed in Table 2 equals the excess NaOH concentration,which can be calculated by the following equation.

[NaOH_(excess)]=[NaOH_(total)]−[NaOH_(needed for neutralization)]

[0113] The in vitro permeation of lidocaine through human cadaver skinfrom these discs was measured as described in the Methods section. Threediffusion cells were used for each formulation. The receiver solution,5% ethanol/95% PBS buffer (0.05 M KH₂PO₄ with 0.15 M NaCl, pH adjustedto 6.5), was completely withdrawn and replaced with fresh receiversolution at each time point. The samples taken were analyzed by an HPLCfor the concentration of lidocaine in the receiver solution. Thecumulative amount of lidocaine across human cadaver skin was calculatedusing the measured lidocaine concentrations in the receiver solutions.TABLE 3 Cumulative Amount of Lidocaine (mg/cm²) Time Lido-1 Lido-2Lido-3 5 hours 0.069 0.126 0.300 15.5 hours 0.237 0.410 0.816 23.75hours 0.428 0.632 1.169

[0114] The pH of the patches was measured as described in the Methodssection. TABLE 4 Excess NaOH Concentration (wt %) and pH Lido-1 Lido-2Lido-3 Excess NaOH 0 3.1% 4.6% Concentration pH 8.86 10.44 10.87

[0115] The pH of the lidocaine patch measured increased from 8.86 to10.87 when the calculated excess NaOH concentration in the dried patchwas increased from 0% to 4.6%. The cumulative amount of lidocaine acrosshuman cadaver skin at 24 hours increased from 0.428 mg/cm² to 1.169mg/cm² when the calculated excess NaOH concentration in the dried patchwas increased from 0% to 4.6%.

[0116] The formulation of Lido-2 provided up to 1.5-fold more lidocaineflux than in the absence of NaOH (Lido-1). The highest pH formulationevaluated, Lido-3, provided up to 3-fold more flux than in the absenceof NaOH.

[0117] All patents, publications, and other published documentsmentioned or referred to in this specification are herein incorporatedby reference in their entirety.

[0118] It is to be understood that while the invention has beendescribed in conjunction with the preferred specific embodiments hereof,the foregoing description, as well as the examples which are intended toillustrate and not limit the scope of the invention, it should beunderstood by those skilled in the art that various changes may be madeand equivalents may be substituted without departing from the scope ofthe invention. Other aspects, advantages and modifications will beapparent to those skilled in the art to which the invention pertains.

[0119] Accordingly, the scope of the invention should therefore bedetermined with reference to the appended claims, along with the fullrange of equivalents to which those claims are entitled.

We claim:
 1. A composition for the enhanced delivery of a localanesthetic agent through a body surface, comprising a formulation of:(a) a therapeutically effective amount of the local anesthetic agent;(b) a pharmaceutically acceptable inorganic base in an amount effectiveto provide a pH within the range of about 8.0-13.0 at the body surfaceduring administration of the local anesthetic agent and to enhance theflux of the local anesthetic agent through the body surface withoutcausing damage thereto; and (c) a pharmaceutically acceptable carriersuitable for topical or transdermal drug administration.
 2. Thecomposition of claim 1 wherein the basic permeation enhancer iscontained within an aqueous formulation.
 3. The composition of claim 2wherein the aqueous formulation has a pH within the range of about8.0-13.0.
 4. The composition of claim 3 wherein the pH is within therange of about 8.0-11.5.
 5. The composition of claim 4 wherein the pH iswithin the range of about 8.5-10.5.
 6. The composition of claim 2wherein the aqueous formulation is selected from the group consisting ofa cream, a gel, a lotion, and a paste.
 7. The composition of claim 1wherein the composition provides for at least about 1.5-fold enhanceddelivery.
 8. The composition of claim 7 wherein the composition providesfor at least about 3-fold enhanced delivery.
 9. The composition of claim1 wherein the local anesthetic agent is an acidic species.
 10. Thecomposition of claim 9 wherein the base is present in an amount that isthe total of (a) the amount required to neutralize the acidic speciesplus (b) an amount equal to about 0.5-4.0 wt % of the composition. 11.The composition of claim 1 wherein the local anesthetic agent is anon-acidic species.
 12. The composition of claim 11 wherein the base ispresent in an amount equal to about 0.5-4.0 wt % of the composition. 13.The composition of claim 1 wherein the base is selected from the groupconsisting of inorganic hydroxides, inorganic oxides, inorganic salts ofweak acids, and combinations thereof.
 14. The composition of claim 13wherein the base is an inorganic hydroxide selected from the groupconsisting of ammonium hydroxide, sodium hydroxide, potassium hydroxide,calcium hydroxide and magnesium hydroxide.
 15. The composition of claim13 wherein the base is an inorganic oxide selected from the groupconsisting of magnesium oxide and calcium oxide.
 16. The composition ofclaim 13 wherein the base is an inorganic salt of a weak acid selectedfrom the group consisting of ammonium phosphate, sodium acetate, sodiumborate, sodium metaborate, sodium carbonate, sodium bicarbonate, sodiumphosphate, potassium carbonate, potassium bicarbonate, potassiumcitrate, potassium acetate, and potassium phosphate.
 17. The compositionof claim 1 wherein the base is effective to provide a pH within therange of about 8.0-11.5 at the localized region of the body surfaceduring administration of the local anesthetic agent.
 18. The compositionof claim 17 wherein the base is effective to provide a pH within therange of about 8.5-10.5 at the localized region of the body surfaceduring administration of the local anesthetic agent.
 19. The compositionof claim 1 wherein the local anesthetic agent is selected from the groupconsisting of benzocaine, benzyl benzoate, bupivacaine, calamine,chloroprocaine, chloroxylenol, cinchocaine, cocaine, dexivacaine,diamocaine, dibucaine, dyclonine, etidocaine, hexylcaine, ketamine,levobupivacaine, lidocaine, menthol, mepivacaine, oxethazaine, phenol,pramoxine, prilocaine, procaine, proparacaine, propoxycaine, pyrrocaine,resorcinol, risocaine, rodocaine, ropivacaine, tetracaine, troclosan,and pharmaceutically acceptable derivatives thereof, and combinationsthereof.
 20. The composition of claim 19 wherein the local anestheticagent is selected from the group consisting bupivacaine, chloroprocaine,dibucaine, etidocaine, levobupivacaine, lidocaine, mepivacaine,prilocaine, ropivacaine, tetracaine, and pharmaceutically acceptablederivatives thereof.
 21. The composition of claim 1 which furthercomprises at least one irritation-mitigating additive.
 22. A system forthe enhanced topical or transdermal administration of a local anestheticagent, comprising: (a) at least one drug reservoir containing the localanesthetic agent and a pharmaceutically acceptable inorganic base, in anamount effective to enhance the flux of the local anesthetic agentthrough the body surface without causing damage thereto; (b) a means formaintaining the system in agent and base transmitting relationship tothe body surface and forming a body surface-system interface; and (c) abacking layer that serves as the outer surface of the system during use,wherein the base is effective to provide a pH within the range of about8.0-13.0 at the body surface-system interface during administration ofthe local anesthetic agent.
 23. The system of claim 22 wherein thebacking layer is occlusive.
 24. The system of claim 22 wherein the drugreservoir is comprised of a polymeric adhesive.
 25. The system of claim24 wherein the polymeric adhesive serves as the means for maintainingthe system in agent and base transmitting relationship to the bodyservice.
 26. The system of claim 22 wherein the drug reservoir iscomprised of a hydrogel.
 27. The system of claim 22 wherein the drugreservoir is comprised of a sealed pouch containing the local anestheticagent and inorganic base in a liquid or semi-solid formulation.
 28. Thesystem of claim 22 wherein the system provides for at least about1.5-fold enhanced delivery.
 29. The system of claim 28 wherein thecomposition provides for at least about 3-fold enhanced delivery. 30.The system of claim 1 wherein the base is effective to provide a pHwithin the range of about 8.0-11.5 at the body surface-system interfaceduring administration of the local anesthetic agent.
 31. The system ofclaim 30 wherein the base is effective to provide a pH within the rangeof about 8.5-10.5 at the body surface-system interface duringadministration of the local anesthetic agent.
 32. The system of claim 22wherein the local anesthetic agent is an acidic species.
 33. The systemof claim 32 wherein the base is present in an amount that is the totalof (a) the amount required to neutralize the acidic species plus (b) anamount equal to about 0.5-4.0 wt % of the drug reservoir.
 34. The systemof claim 22 wherein the local anesthetic agent is a non-acidic species.35. The system of claim 34 wherein the base is present in an amountequal to about 0.5-4.0 wt % of the drug reservoir.
 36. The system ofclaim 22 wherein the base is selected from the group consisting ofinorganic hydroxides, inorganic oxides, inorganic salts of weak acids,and combinations thereof.
 37. The system of claim 36 wherein the base isan inorganic hydroxide selected from the group consisting of ammoniumhydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide andmagnesium hydroxide.
 38. The system of claim 36 wherein the base is aninorganic oxide selected from the group consisting of magnesium oxideand calcium oxide.
 39. The system of claim 36 wherein the base is aninorganic salt of a weak acid selected from the group consisting ofammonium phosphate, sodium acetate, sodium borate, sodium metaborate,sodium carbonate, sodium bicarbonate, sodium phosphate, potassiumcarbonate, potassium bicarbonate, potassium citrate, potassium acetate,and potassium phosphate.
 40. The system of claim 22 wherein the localanesthetic agent is selected from the group consisting of benzocaine,benzyl benzoate, bupivacaine, calamine, chloroprocaine, chloroxylenol,cinchocaine, cocaine, dexivacaine, diamocaine, dibucaine, dyclonine,etidocaine, hexylcaine, ketamine, levobupivacaine, lidocaine, menthol,mepivacaine, oxethazaine, phenol, pramoxine, prilocaine, procaine,proparacaine, propoxycaine, pyrrocaine, resorcinol, risocaine,rodocaine, ropivacaine, tetracaine, troclosan, and pharmaceuticallyacceptable derivatives thereof, and combinations thereof.
 41. The systemof claim 40 wherein the local anesthetic agent is selected from thegroup consisting of bupivacaine, chloroprocaine, dibucaine, etidocaine,levobupivacaine, lidocaine, mepivacaine, prilocaine, ropivacaine,tetracaine, and pharmaceutically acceptable derivatives thereof.
 42. Thesystem of claim 22 which further comprises at least oneirritation-mitigating additive.